Is cytokine removal by continuous hemofiltration feasible?
Authors: Heinz-Gunter Sieberth, Horst P. Kierdorf
Journal: Kidney International (1999)

Is cytokine removal by continuous hemofiltration feasible? Patients who are critically ill with acute renal failure and sepsis have extremely high mortality rates. While it seems reasonable that eliminating the inflammatory mediators (such as cytokines, chemokines, tumor necrosis factor-α, etc.) by continuous renal replacement therapy (CRRT) would be effective, studies show that only insubstantial numbers of these mediators are removed in comparison with endogenous clearance. Mass removal seems only to be effective when highly permeable membranes (sieving coefficient of approximately 1.0) are used, there is a filtrate volume greater than 2 liters/hour, and when the half-life of the substance to be eliminated is greater than 60 minutes. Removal of cytokines by membrane adsorption is another possibility. However, because the membrane surfaces are saturated after a few hours, frequent filter changes are necessary for them to generate effective adsorption of these mediators. Despite filter changes, only a brief and transient drop in the TNF plasma level has been observed. Controlled clinical trials are needed to determine whether or not CRRT actually has a beneficial effect on the systemic inflammatory response syndrome (SIRS). Is cytokine removal by continuous hemofiltration feasible? Patients who are critically ill with acute renal failure and sepsis have extremely high mortality rates. While it seems reasonable that eliminating the inflammatory mediators (such as cytokines, chemokines, tumor necrosis factor-α, etc.) by continuous renal replacement therapy (CRRT) would be effective, studies show that only insubstantial numbers of these mediators are removed in comparison with endogenous clearance. Mass removal seems only to be effective when highly permeable membranes (sieving coefficient of approximately 1.0) are used, there is a filtrate volume greater than 2 liters/hour, and when the half-life of the substance to be eliminated is greater than 60 minutes. Removal of cytokines by membrane adsorption is another possibility. However, because the membrane surfaces are saturated after a few hours, frequent filter changes are necessary for them to generate effective adsorption of these mediators. Despite filter changes, only a brief and transient drop in the TNF plasma level has been observed. Controlled clinical trials are needed to determine whether or not CRRT actually has a beneficial effect on the systemic inflammatory response syndrome (SIRS). A great number of supporting and hampering factors are involved in the complex network that leads to sepsis. These include cytokines, chemokines, adhesion molecules, E-selectin, prostaglandins, and various phagocytic cells of the immune system, the systemic inflammatory response syndrome (SIRS) and the counter-regulatory anti-inflammatory response syndrome (CARS). The inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) cause the same spectrum of clinical symptoms as do staphylococcal exotoxin or gram-negative endotoxins. IL-6, IL-8, and platelet-activating factor are further important elements that stimulate inflammation. Extensive experimental and clinical investigations are now being focused on the concept of blocking the biological properties of IL-1 and TNF. Blocking IL-1 or TNF-α has been highly successful in patients with rheumatoid arthritis, inflammatory bowel disease, or graft-versus-host reaction. However, despite positive experience with animal models, anticytokine therapy for sepsis has been disappointing. Over 13,000 patients with septic shock have entered trials with TNF-α–neutralizing antibodies, soluble TNF-α receptors, and IL-1 receptor antagonists in double-blind, placebo controlled trials1Calandra T. Immunomodulation for Sepsis and Septic Shock.1998Google Scholar, 2Fisher Jr, C.J. Dhainaut J.F. Opal S.M. Pribble J.P. Balk R.A. Slotman G.J. Iberti T.J. Rackow E.C. Shapiro M.J. Greenman R.L. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome: Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group.JAMA. 1994; 271: 1836-1843Crossref PubMed Scopus (951) Google Scholar, 3McCloskey R.V. Straube R.C. Sanders C. Smith S.M. Smith C.R. Treatment of septic shock with human monoclonal antibody HA-1A.A randomized, double-blind, placebo-controlled trial: CHESS Trial Study Group.Ann Intern Med. 1994; 121: 1-5Crossref PubMed Scopus (408) Google Scholar, 4Abraham E. Wunderink R. 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However, it has not been proven that these symptoms are caused by mediators, as it is possible that filtered exotoxins may induce the septic symptoms32Lee P.A. Matson J.R. Pryor R.W. Hinshaw L.B. Continuous arteriovenous hemofiltration therapy for Staphylococcus aureus-induced septicemia in immature swine?.Crit Care Med. 1993; 21: 914-924Crossref PubMed Scopus (97) Google Scholar. Hemofiltration has shown no beneficial effect in animal models in which an infection such as peritonitis, instead of exotoxins or indotoxins, was employed to induce sepsis33Freeman B.D. Yatsiv I. Natanson C. Solomon M.A. Quezado Z.M.N. Danner R.L. Banks S.M. Hoffman W. Continuous arteriovenous hemofiltration does not improve survival in a canine model of septic shock.J Am Coll Surg. 1995; 180: 286-292PubMed Google Scholar. A series of investigations has shown that hemofiltration does remove cytokines from the circulation by convection20Bellomo R. Tipping P. Boyce N. 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Commonly, removal is expressed as a percentage of the blood or plasma concentration, and not as a portion of the total body amount or with respect to the metabolic clearance rate. Effective blood purification, and also in the case of mediators, generally takes place under three conditions: (a) The extracorporeally eliminated amount must be of consequence when regarding the total body amount. (b) With respect to the endogenous clearance rate, the extracorporeal clearance rate must be so high that (c) the amount eliminated extracorporeally beneficially influences the course of the disease. It is not clear whether or not the elimination of isolated sepsis or SIRS-related factors can influence the course of the disease. It is also possible that removal of isolated mediators after a prolonged course of the disease is no longer beneficial. According to Fong et al, "Hence, the entire milieu of hormonal and cytokine mediators must be considered in the assessment of postinjury biologic response"40Fong J. Moldawer L.L. Shires G.T. Lowry S.F. The biological characteristics of cytokines and their implication in surgical injury.Surg Gynecol Obstet. 1990; 170: 365-378Google Scholar. To judge the quality of an elimination process, it is necessary to determine not only a concentration difference but the total amount eliminated (mass removal). The appropriate measurements are shown in Table 1. Because cytokines occur in different fluids, internal standards should be contained in those fluids under investigation. It should be kept in mind that values attained with an enzyme-linked immunosorbent assay (ELISA) may not be the same as those achieved with a bioassay. This is particularly true for TNF-α, which is inactive in the monomeric form but active in the trimeric form.Table 1Extracorporeal mass removal (mass removal during endogenous half-life) Open table in a new tab Before judging the efficiency of a procedure, the amount of a substance eliminated extracorporeally must be established in relationship to the endogenous clearance Table 2.Table 2Efficacy of blood purification Open table in a new tab Aside from the parameters listed in Table 1, the following parameters are necessary for a calculation: molecular weight41Callard R. Gearing A. The Cytokine Facts Book. Academic Press Harcourt Brace & Company, London, San Diego1994Google Scholar, sieving coefficient in vivo10Schetz M. Non-renal indications for CRRT.Kidney Int. 1999; 56 (this issue)Google Scholar, 20Bellomo R. Tipping P. Boyce N. 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Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.Ren Fail. 1997; 19: 443-454Crossref PubMed Scopus (48) Google Scholar, 42Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Cytokine kinetics (TNF-alpha, IL-1beta, IL-6) during continuous hemofiltration: A laboratory and clinical study.Contrib Nephrol. 1995; 116: 62-75Crossref PubMed Google Scholar, virtual distribution volume in the body43Blick M. Sherwin S.A. Rosenblum M. Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients.Cancer Res. 1987; 47: 2986-2989PubMed Google Scholar, and internal elimination rate (half-life)40Fong J. Moldawer L.L. Shires G.T. Lowry S.F. The biological characteristics of cytokines and their implication in surgical injury.Surg Gynecol Obstet. 1990; 170: 365-378Google Scholar, 43Blick M. Sherwin S.A. Rosenblum M. Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients.Cancer Res. 1987; 47: 2986-2989PubMed Google Scholar, 44Lotze M.T. Robb R.J. Sharrow S.A. Systemic administration of interleukin-2 in humans.J Biol Response Mod. 1984; 3: 475-482PubMed Google Scholar, 45Beutler B.A. Milsark I.W. Cerami A. Cachectin/tumor necrosis factor: Production, distribution, and metabolic fate in vivo.J Immunol. 1985; 135: 3972-3977PubMed Google Scholar, 46Newton R.C. Uhl J. Covington M. Back O. The distribution and clearance of radiolabeled human interleukin-1 beta in mice.Lymphokine Res. 1988; 7: 207-216PubMed Google Scholar, 47Lowry S.F. Van Zee K.J. Rock C.S. Thompson W.A. Oldenburg H.S.A. Rogy M.A. Moldawer L.L. Tumor necrosis factor as a mediator of sepsis.in: Schlag G.A. Redl H. Shock, Sepsis and Organ Failure. Springer, Berlin, Heidelberg1993: 13-14Crossref Google Scholar, 48Moldawer L.L. Fischer E. Van Lee K.J. Thompson W.A. Lowry S.F. A role for interleukin-1 in septic shock.in: Schlag G.A. Redl H. Shock, Sepsis and Organ Failure. Springer, Berlin, Heidelberg1993: 18-25Crossref Google Scholar, 49Castell J. Klapproth J. Gross V. Eike W.E. Andus T. Snyers L. Content J. Heinrich P.C. Fate of interleukin-6 in the rat.Eur J Biochem. 1990; 189: 113-118Crossref PubMed Scopus (44) Google Scholar, 50Borth W. Luger T.A. Identification of α2-macroglobulin as a cytokine binding plasma protein.J Biol Chem. 1989; 264: 5818-5825Abstract Full Text PDF PubMed Google Scholar. These reference data are listed in Table 3. Considering their molecular weights, a higher sieving coefficient could be expected for most of the cytokines. However, binding to circulating receptors or other proteins and secondary membrane formation in the hemofilters result in a decrease in the sieving coefficient. That may be one reason why the coefficients vary considerably between investigators, between different membrane types, and are not constant during the course of filtration. However, because of the short metabolic half-life, this variability is of little significance when purifying the blood of cytokines.Table 3Molecular weight, sieving coefficients and endogenous half-lives of some cytokinesCytokinesMolecular weightSieving coefficientHalf-life minutesTNFα∼17.40–0.2,aData are from the literature10 0.01–1.052De Vriese A.S. Colardyn F.A. Philippe J.J. Vanholder R.C. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar∼6–745Beutler B.A. Milsark I.W. Cerami A. Cachectin/tumor necrosis factor: Production, distribution, and metabolic fate in vivo.J Immunol. 1985; 135: 3972-3977PubMed Google Scholar ∼14–1743Blick M. Sherwin S.A. Rosenblum M. Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients.Cancer Res. 1987; 47: 2986-2989PubMed Google Scholar monomer∼1547Lowry S.F. Van Zee K.J. Rock C.S. Thompson W.A. Oldenburg H.S.A. Rogy M.A. Moldawer L.L. Tumor necrosis factor as a mediator of sepsis.in: Schlag G.A. Redl H. Shock, Sepsis and Organ Failure. Springer, Berlin, Heidelberg1993: 13-14Crossref Google Scholar trimer∼52IL-1∼180.07–0.42,bRising sieving coefficient during hemofiltration 0.3538Hoffmann J.N. Hartl W.H. Deppisch R. Faist E. Jochum M. Inthorn D. Hemofiltration in human sepsis: Evidence for elimination of immunomodulatory substances.Kidney Int. 1995; 48: 1563-1570Abstract Full Text PDF PubMed Scopus (124) Google Scholar 0.1839Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.Ren Fail. 1997; 19: 443-454Crossref PubMed Scopus (48) Google Scholar, 0.12–1.052De Vriese A.S. Colardyn F.A. Philippe J.J. Vanholder R.C. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar∼6–1044Lotze M.T. Robb R.J. Sharrow S.A. Systemic administration of interleukin-2 in humans.J Biol Response Mod. 1984; 3: 475-482PubMed Google ScholarIL-2∼6–1046Newton R.C. Uhl J. Covington M. Back O. The distribution and clearance of radiolabeled human interleukin-1 beta in mice.Lymphokine Res. 1988; 7: 207-216PubMed Google ScholarIL-6∼260.01–0.3252De Vriese A.S. Colardyn F.A. Philippe J.J. Vanholder R.C. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar∼649Castell J. Klapproth J. Gross V. Eike W.E. Andus T. Snyers L. Content J. Heinrich P.C. Fate of interleukin-6 in the rat.Eur J Biochem. 1990; 189: 113-118Crossref PubMed Scopus (44) Google ScholarIL-8∼6–80.0–0.48,bRising sieving coefficient during hemofiltration 0.4439Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Impact of continuous hemofiltration on cytokines and cytokine inhibitors in oliguric patients suffering from systemic inflammatory response syndrome.Ren Fail. 1997; 19: 443-454Crossref PubMed Scopus (48) Google Scholara Data are from the literature10Schetz M. Non-renal indications for CRRT.Kidney Int. 1999; 56 (this issue)Google Scholarb Rising sieving coefficient during hemofiltration Open table in a new tab The distribution volume of cytokines with a molecular weight below 20 kDa should correspond to at least the extracorporeal space, which entails approximately 15% of the body weight. Determination of the half-life of the cytokines raises some problems. It is possible to estimate the half-life after one dose of a labeled cytokine49Castell J. Klapproth J. Gross V. Eike W.E. Andus T. Snyers L. Content J. Heinrich P.C. Fate of interleukin-6 in the rat.Eur J Biochem. 1990; 189: 113-118Crossref PubMed Scopus (44) Google Scholar or by the slope of the curve after a single application of an exotoxin or endotoxin. However, continuous formation of cytokines must be considered47Lowry S.F. Van Zee K.J. Rock C.S. Thompson W.A. Oldenburg H.S.A. Rogy M.A. Moldawer L.L. Tumor necrosis factor as a mediator of sepsis.in: Schlag G.A. Redl H. Shock, Sepsis and Organ Failure. Springer, Berlin, Heidelberg1993: 13-14Crossref Google Scholar. No reference data are available for the half-life of cytokines in patients with SIRS, where increased formation occurs. For the subsequent calculations, a half-life for TNF-α of 15 minutes has been employed, which corresponds to the half-life of other cytokines. An extracellular space of 15 liters and a filtration volume of 1 liter/hr and a relatively high sieving coefficient for TNF-α of 0.25 are assumed. With a plasma TNF-α concentration of 500 pg/ml or 500 ng/liter and an extracellular volume of 15 liters, a total amount of approximately 7500 ng TNF-α is calculated. During the 15-minute half-life, roughly 3750 ng are metabolized while at the same time, 250 ml filtrate with approximately 30 ng TNF-α is removed. Comparing the metabolized amount of TNF-α and the amount removed by hemofiltration, a mass transfer by hemofiltration of only approximately 1% occurs. Increasing the sieving coefficient to 1 increases the amount removed by hemofiltration to approximately 4%. In Table 4, the mass removal of a single mediator with different filtrate volumes and sieving coefficients is calculated. The calculation with higher sieving coefficients demonstrates the mass transfer that can occur with membrane improvement. Because no data are available about the half-life of mediators in patients with sepsis or SIRS, the calculations are carried out with half-lives of up to 120 minutes.Table 4Mass removal by hemofiltration (%) in relation to the endogenous half-life and dependence of filtrate volume and the sieving coefficientFiltrate volumeSieving coefficientHalf-life of mediator, 100% endogenously removed15 min30 min60 min120 min1 liter/hr0.10.30.61.22.41 liter/hr0.2512481 liter/hr0.5248161 liter/hr14816322 liter/hr0.10.61.22.44.82 liter/hr0.25248162 liter/hr0.54816322 liter/hr1.08163264 Open table in a new tab The question of whether continual renal replacement therapy (CRRT) has a beneficial effect on sepsis or SIRS can be clarified only in controlled studies. Whether or not substantial amounts of various mediators can be removed by hemofiltration must be established by measurement. The results presented here with relevant data show that hemofiltration can only remove insubstantial amounts of mediators, representing only a few percentages, compared with endogenous clearance. In concurrence, most investigators have reported no (abstract; Kierdorf et al, Ren Fail 14:98, 1992)27Wakabayashi Y. Kamijou Y. Soma K. Ohwada T. Removal of circulating cytokines by continuous hemofiltration in patients with systemic inflammatory response syndrome of multiple organ dysfunction syndrome.Br J Surg. 1996; 83: 393-394Crossref PubMed Scopus (31) Google Scholar,42Van Bommel E.F.H. Hesse C.J. Jutte N.H.P.M. Zietse R. Bruining H.A. Weimar W. Cytokine kinetics (TNF-alpha, IL-1beta, IL-6) during continuous hemofiltration: A laboratory and clinical study.Contrib Nephrol. 1995; 116: 62-75Crossref PubMed Google Scholar or only minimal decreases in the plasma mediator concentration51Kellum J.A. Johnson J.P. Kramer S. Palevsky P. Brady J.J. Pinsky M.R. Diffusive versus convective therapy: Effects on mediators of inflammation in patient with severe systemic inflammatory response syndrome.Crit Care Med. 1998; 26: 1995-2000Crossref PubMed Scopus (199) Google Scholar, even when employing hemofiltration over several days. An effective mass removal is only possible with a highly permeable membrane (sieving coefficient approximately 1.0), a high filtrate volume (≥2 liter/hr), and when the half-life of the substance to be eliminated is greater than 60 minutes. Membrane adsorption has not been taken into account in these calculations. Adsorption onto the majority of membranes generally in use is low and only for polyacrylonitrile membranes relatively high52De Vriese A.S. Colardyn F.A. Philippe J.J. Vanholder R.C. De Sutter J.H. Lameire N.H. Cytokine removal during continuous hemofiltration in septic patients.J Am Soc Nephrol. 1999; 10: 846-853PubMed Google Scholar. However, within a few hours, the adsorption on the membrane surface is saturated. Frequent filter change or developing special filters might generate more efficient adsorption, perhaps with better mass removal of mediators encountered during sepsis, but even during treatment with this type of membrane, only a short transient drop of the TNF plasma level could be observed. Following disappointing results of treating sepsis or SIRS with antibodies and receptor blockers for cytokines, hope had been invested in removing these substances by blood purification. The calculations presented here show that continuous hemofiltration can remove only insubstantial amounts of mediators when compared with endogenous clearance. This does not mean that continuous renal replacement therapy (CRRT) cannot positively influence sepsis or SIRS in other ways.